CALCIUM INFLUX VIA IONOTROPIC GLUTAMATE RECEPTORS CAUSES LONG-LASTINGINHIBITION OF METABOTROPIC GLUTAMATE RECEPTOR-COUPLED PHOSPHOINOSITIDE HYDROLYSIS

Functional interaction between ionotropic and metabotropic glutamate r eceptors (iGluR and mGluR respectively) was studied in cerebellar gran ule cell cultures using quisqualate (QA), the most potent agonist of p hosphoinositide hydrolysis coupled mGluR, and N-methyl-D-aspartate (NM DA) or kainate (KA) that activate different classes of iGluR. Two h ex posure to NMDA or KA resulted in a marked reduction (about 75%) of QA- evoked PI hydrolysis. The efficacy of the two agonists was about the s ame, but the potencies were different (IC50 for NMDA about 35 mu M and for KA about 70 mu M). NMDA-induced depression of QA-stimulated PI hy drolysis was relatively long lasting but reversible. Recovery required protein synthesis. In nominally Ca2+-free medium both NMDA and KA fai led to attenuate QA-stimulated PI hydrolysis. The effect of NMDA was p revented by the NMDA receptor antagonist MK801, but not by the wide sp ectrum protein kinase inhibitor staurosporin nor by the nitric oxide s ynthase inhibitor N omega-nitro-L-arginine. Cycloheximide and concanav alin A were also ineffective. The effect of KA was prevented by the se lective non-NMDA receptor antagonist -dihydroxy-6-nitro-7-sulfamoyl-be nzo(F)quinoxaline (NBQX). Voltage sensitive Ca2+ channel antagonists t ogether with MK801 did not counteract the inhibition by KA of the QA r esponse. Both NMDA and KA attenuated PI hydrolysis evoked by the musca rinic receptor agonist carbachol (about 30%), indicating that the acti vation of iGluRs exerts a relatively general inhibitory effect on the function of different PLC-coupled metabotropic receptors. Consistent w ith this observation is that treatments either with KA and NMDA induce d an inhibition (about 30%) of NaF-stimulated PI hydrolysis which occu rs through the direct activation of G proteins. Our observations show that ionotropic glutamate receptor stimulation induces a long lasting suppression of QA-evoked PI breakdown through a Ca2+ dependent mechani sm which seems to involve receptor coupled transduction systems downst ream from mGluR. Such a Ca2+-dependent cross-talk involving ionotropic and metabotropic receptors may play a role in certain events of synap tic plasticity. (C) 1998 Elsevier Science Ltd. All rights reserved.